9alpha-halo and 9beta, 11beta-epoxy steroids of the pregnane series and processes for preparing the same



9a-HALO AND 9,3,11,8-EPOXY STEROIDS OF THE PREGNANE SERIES AND PROCESSES FOR PRE- PARING THE SAlVE Josef Fried and Josef E. Herz, New Brunswick, N.J., as-

signors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia N Drawing. Filed Oct. 19, 1956, Ser. No. 616,944

16 Claims. (Cl. 260-23955) This application is a continuation-in-part of our patent application, Serial No. 585,155, filed May 16, 1956.

This invention relates to the synthesis of valuable steroids and has for its objects the provision of: (I) an advantageous process of preparing steroids of the A -18- nor-17wpregnadiene (including the 18-n0r-17a-pregnatrienes) series having a 9oz-llal0 substituent, and an ll-keto, 11B-hydroxy or IIB-aoyloxy substituent; (II) certain new compounds useful themselves as physiologically active steroids; and (Ill) certain new compounds useful in the preparation of said physiologically active steroids.

The process of this invention essentially comprises: (a) interacthr a ll-organic sulfonic acid ester of 96,11,3- epoxy A pregnene-17a,21-diol-3,20-dione or 95,11,3- epoxy-A -pregnadiened7a,21-diol-3,20-dione with anhydrous potassium fluoride to yield, inter alia, A pregnene- 9,3,1118;17a,21-dioxido-3,20-dione and A -pregnadiene- 96,11;8;17a,21-dioXido-3,ZO-dione, respectively; (b) treating the latter compounds with a hydrogen halide to yield the corresponding 90L-l'13JlO-11fi-hYdI'OXY derivatives; (0) oxidizing these 9a-halo-11B-hydroxy derivatives, if desired, to the corresponding 90: halo 11 keto derivatives; (d) rearranging the 9a-halo-11fl-hydroxy derivatives, either by heating with a dilute acid or by treating with hydrogen fluoride, to the corresponding 9 x-halo- 1713 methyl-17a-pregnene-13a,21-cxido-11fl-0l-3,20-dione or 9rx-halo-A -17fl-methyl-18-nor-17u-pregnadiene 13a, 21-oxido-11fi-ol-3,20-dione derivatives, respectively; (e) oxidizing these llfi-hydroxy steroids, if desired, to the corresponding 11-ketones; and (f) treating the 11/3- hydroxy norpregnanes with hydrogen fluoride to yield 9ozhalo-A -17B-meth1y1-17a-pregnadiene-115,21-diol 3,20- dione or 9ot-halo-A -17B-metl1yl-17a-pregnatriene-11B, 21-diol-3,20-dione, respectively, which in turn can in the usual manner be oxidized to their ll-keto derivatives (after protection of the 21-hydroxyl group by mo'noacetylation), monoesterified to yield a 21-monoester, or diesterified (if an llfi-hydroxy starting material is used) to yield an 11,6,21-diester derivative. The Qa-flnoro-A pregnene-17a,21oxido-11p-ol-3,20-dione and 9a-fluoro- A -pregnadiene 17a,21 oxido-11;8-ol-3,20-dione derivatives of this invention can also be prepared directly from 21-organic sulfonic acid esters of 9m-fluorohydrocortisone or Qa-fiuoro-A pregnadiene-11B,17a,21-tri0l-3,2O-dione, as disclosed in said Serial No. 585,155, by interaction of the sulfonic acid esters with potassium fluoride. The final A -steroids can also be prepared directly from the 1700, 21-epoxide derivatives, without isolation of the rearranged intermediates, by treating the latter with hydrogen fluoride.

The novel compounds of this invention comprise: (A) intermediate steroids of the general formula tats atent Q a 3,907,925 Patented Nov. 7, 1961 2 (B) intermediate 9oc-h310 steroids, which possess glucocorticoid activity and hence can be used in lieu of hydrocortisone in the treatment of rheumatoid arthritis, of the general formula wherein the 1,2-position is saturated or double-bonded, R is hydrogen, R is fi-hydroxy, or together R and R is keto, and X is tit-halogen (preferably fluoro); (C) intermediate 9a-hal-o-17m-pregnenes of the general formula crazy i i=0 i 0 H3 wherein the 1,2- posi-tion is saturated or double-bonded, R" is hydrogen, R is fi-hydroxy or B-acylox-y, or together R and R' is keto, X is a-h-alogen (preferably fluoro), and Y is hydroxy or acyloxy. In both instances, the acyloxy substituent is preferably the acyloxy radical of a hydrocarbon carboxylic acid having less than ten carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic acid), the lower alkanoic acids (e.g., acrylic acid), the monocyclic aromatic carboxylic acids (e.g., benzoic acid), the monocyclic aromatic lower alkanoic acids (e.g., phenacetic acid), the cyclo(lower alkyl)carboxylic acids (e.g., cyclopropanecarboxylic acid) and the carboxyl acid).

The process of this invention can be illustrated by the following equations:

(EH 0 solo H1 0:0 LHOH 1 if KF 2 s HA V.

VI VII VIII IX X.

t wy I. 1,2-saturated II. 1,2-double-bonded dione (Compound 1V) from the organic sulfonic acid esters (e.g., mesylates) of 9ot-fiuorohydroccrtisone and To compounds III through X To prepare the diepoxides of this invention (Compounds I and II), a 21-organic sulfonic acid ester of 96,115-epoxy-A -pregnene-lhjl-diol-3,20-dione or 9,8, 11,3 epoxy-N- pregnadiene-17a,21-dio1-3,20-dione e.g., a lower alk'anesulfonate, such as mesylate, and an aryl sulfonate, such as tosylate) is reacted with potassium fluoride. This reaction is preferably conducted under substantially-anhydrous conditions in an organic solvent of high. dielectric constant, such as dimethylformami'de,

dimethy'lsulfoxide or diethylene, glycol, optimally at an elevated. temperature (e.g., 90-120 C) This process also affords a direct method for preparing 9 uflu0ro-A pregnene-l7u,21-oxido-11fi-ol-3,20-dione (Compound III) and 9a-fiuoro-A -pregnadiene-17a,21-oxido-1 1/3-ol-3,20

through V1) can then be rearranged to the 17u-pregnene (or pregnadiene) derivatives by either heating with a dilute acid (HA), such as dilute mineral acid as exemplified by dilute sulfuric acid, the heating being preferably done in the temperature range of about 60 C. to about 100 C., or by treatment with hydrogen fluoride in an organic solvent at a low temperature (e.g., below room temperature) for a short period of time (e.g., about 30 minutes).

The reaction results in the formation of a 9a-halo-A (or A -17/3 methyl-17upregnene-( or pregnadiene)-13a, 2l-oxido-11,8-ol-3,20-dione (e.g., Compounds XI through XIV), which can be oxidized in the usual manner to the l1-keto derivatives (e.g., Compounds XV through XV III) or treated with hydrogen fluoride for more than thirty minutes to yield the 9a-halo-A -(or A -17dmethyl-17apregnadiene-( or pregnatriene)-1 1,8,21-dio1-3 ,ZO-dione final products of this invention (e.g., Compounds XIX through XXII). If an 11-k6t0 steroid is desired, the initially resulting llfi-hydroxy steroid can be oxidized with chromic acid (after protection of the 21-hydroxyl group as by monoacetylation to the ketones, e.g., Compounds XXIII through XXVI), which in turn can be saponified in the usual manner, as by treatment with potassium carbonate, to yield the free l-l-keto-Zl-hydroxy derivatives. To prepare Zl-esters, the IIB-hydroxy steroids are reacted with an acylating agent, such as an acid anhydride or an acyl halide (e.g., acetic anhydride or benzoyl chloride), in the presence of a tertiary base (e.g., pyridine). The nature of the ester derivative will depend on the mole ratio of esterifying reagent to steroid. If a one to one mole ratio is used, then a 21-monoester is formed; if, however, two or more moles of acylating agent is employed per mole of steroid, then an 115,21-diester is the product.

The A -steroids can also be formed directly from the 17a,2l-epoxy steroids (Without separation of the initial rearranged intermediate) by treating the latter with hydrogen fluoride for more than thirty minutes.

The following examples illustrate the invention (all temperatures being in centigrade):

1.0 g. of 95,1lfl-epoxy-n -pregnene-17c:,21-diol3,20- dione 2l-mcsylate and 1.0 g. of anhydrous potassium fluoride are heated in 50 ml. of freshly distilled dimethylsulfoxide with stirring at 110 for 18 hours. The mixture is concentrated in vacuo, the residue 10 ml.) taken up in ethyl acetate and the ethyl acetate extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The semicrystalline residue (about 770 mg.) is treated with 20 ml. of benzene, the resulting suspension centrifuged and the benzene solution chromatographed on 15 g. of acid-washed alumina. Elution with benzene (1000 ml.) produces about 115 mg. of crystalline A -pregnene-9fl,l1,8;17a,21-dioxido-3,20-dione, which after recrystallization from 95% alcohol has the following properties: M.P. about 196-199"; [a] +59 (0., 1.02 in chloroform);

its, 243 mu (6 16,200); was? no on; 5.52;. 6.0.. 6.17,.

Analysis.Calcd. for C I-1 (342.42): C, 73.66; H, 7.66. Found: C, 73.62; H, 7.77.

The above-mentioned precipitate obtained after removal of the benzene-soluble l7a,2l-epoxide (I) by centrifugation is recrystallized from acetone-hexane and furnishes 21fluoro-A -pregnene-9fl,l 113 oxido 17a ol- 3,20-dione of the following properties: M.P. about 245- 246; [a] 11.5 (c., 0.37 in acetone);

1123-, 243m (e=15,500); Afig'if 2.87;, 5.80 6.10

Analysis.Calcd. for C H O F (362.43): C, 69.59; H, 7.51; F, 5.24. Found: C, 69.50; H, 7.63; F, 5.26.

6 EXAMPLE 2 A -pregnadz'ene-9B,115;] 7a,21-di0xid0-3,20-dione (II) Following the procedure of Example 1, but substituting 918,1lfi-epoxy-A -pregnadiene-17,21 diol 3,20 dione 21-n1esylate for the mesylate of the example, there is obtained A -pregnadiene-9[3,11 8;17a,21 dioxide 3,20- dione (I1) and 21-fluoro-A -pregnadiene-9B,l1B oxido- 17 aol-3,20-dione.

EXAMPLE 3 9or-flu0r0-A -pregnerle-l 701,21 -0xid0-1 1 [3-01-32 O-dione (III To a solution of 200 mg. of 9a-fiuorohydrocort1'sone 21-mesylate in 5 ml. ofredistilled dimethylformamide is added 200 ml. of anhydrous potassium fluoride, and the resulting suspension is heated with stirring at 110 for 18 hours. The mixture is concentrated to small volume, taken up in water and extracted with ethyl acetate. The ethyl acetate extract is in turn extracted with water, dried over sodium sulfate and the solvent removed in vacuo. The residue is triturated with chloroform, and the chloroform solution, from which the insoluble 9a,21-difluoro- M-pregenel15,17ot-diol-3,20-dione concurrently formed has been removed, is concentrated in vacuo. The residue obtained is recrystallized from ethanol to yield 9afiuoro-A -pregnene-17a,21-oxido 11,6 o1 3,20 dione having the following properties: M.P. about 272274; [a] |l86 (0., 0.57 in chloroform);

rag 2.37 m (e 18,300); 3.00,., 5.55.., sna 0.1m 6.19

Analysis.-Calcd. for C I-1 0 1 (362.43): C, 69.61; H, 7.51; F, 5.37. Found: C, 69.77; H, 7.77; F, 5.65.

EXAMPLE 4 To a solution of 217 mg. of 9a-fluoro-n -pregnadiene- 11B,l7a,2l-triol-3,20-dione 21-mesylate in 10 ml. of dimethylformamide is added 220 mg. of anhydrous potassium fluoride. The reaction conditions are the same as in Example 3. The residue from the ethyl acetate extract is triturated with chloroform, and the chloroform filtrate, after separating off the insoluble 9a,21-difluoro A -pregnadiene-11B,17a-diol-3,2O-dione, is evaporated in vacuo to leave a residue which is recrystallized from 95% ethanol to yield 9a-fluoro-A -pregnadiene-17u,21-oxido- 11B-ol-3,20-dione having the following properties: M.P. about 227-228; [d]D +181 (c., 0.47 in chloroform);

Ami? 2.9511, 5.52 5.0441, 6.17 J., 6.24;:

EXAMPLE 5 To a solution of 770 mg. of 9a-fiuor0-A -pregnadieno l1B-17cc,21-triol-3,20-dione 21-mesylate in 33 ml. of dimethylsulfoxide is added 770 mg. of anhydrous potassium fluoride. The reaction conditions are the same as in Example 3. The residue from the ethyl acetate extract is triturated with chloroform and the chloroform filtrate, after separating off the insoluble 9a,21-difluoro- A -pregnadiene-11,8,17a-diol-3,20-dione, is evaporated in vacuo to leave a residue (about 350 mg.) which is dissolved in 20 ml. of chloroform and 20 ml. of benzene and chromatographed on 7 g. of acid-washed alumina. Elution with 500 ml. of chloroform-benzene (1:1) furnishes about 220 mg. of crystalline material, which after recrystallization from 95% ethanol yields 9a-fluoro-A pregnadiene-l7u,21-oxido-1Idol-3,20 dione having the following properties: M.P. about 308-310; [(11 4- 183 (c., 0.47 in chloroform);

max.

'7 Analysis.Calcd. for C H O F (360.41): C, 69.98; H, 6.99. Found: C, 69.85; H, 6.96.

EXAMPLE 6 To a solution of 500 mg. of A -pregnene-95,116;17 x,21- dioxido-3,20-dione in 50 ml. of chloroform is added at 7.5 m1. of 0.57 N hydrogen chloride in chloroform. The mixture is allowed to remain at 0 for one hour and then extracted with Water, dilute sodium bicarbonate and again with water. The chloroform solution is dried over sodium sulfate and the solvent removed in vacuo. The residue, after crystallization from 95% alcohol, furnishes pure 9a-chloro-A -pregnene-17a,21-oxido-11,8 o1 3,20- dione (V).

In a similar manner, if hydrogen bromide or hydrogen iodide is substituted for the hydrogen chloride in the procedure of Example 6, there is obtained 9zx-bromo- M-pregnene-l7a,21-oxido-11/3-ol-3,20-dione and 9a-iodo- A -pregnene-17a,2l-oxido-1lfi-ol-3,20-dione, respectively.

EXAMPLE 7 Following the procedure of Example 6, but substituting an equivalent amount of A -pregn adiene-9fi,lM21704, 21-dioxido-3,20-dione for the A -pregnene-9fi,11,8;l7a,21- dioxido-3,20-dione, there is obtained 9a-ch1oro-A pregnadiene-17a,21-oxido-1lfi-ol-3,20-dione (VI).

EXAMPLE 8 9a-fluor0-A pregnene-17e,21 -0xido-3 ,1 1 ,ZO-triane (VIZ To a solution of 100 mg. of 9a-fluoro-A -pregnene-17a, 21-oxido-11fi-ol-3,20-dione in ml. of glacial acetic acid is added a solution of 35 mg. of chromic acid in 3.5 ml. of glacial acetic acid. The mixture is allowed to remain at room temperature for 30 minutes; and after addition of 0.5 ml. of alcohol, the solution is concentrated to a small volume in vacuo. The concentrate is extracted with chloroform, and the chloroform extract is washed with water, dilute bicarbonate and again with water, dried over sodium sulfate, and the solvent removed in vacuo. The resulting 9a-fluoro-A -pregnene-17oz,21-oxido-3,l1,20-trione is recrystallized from acetone.

Similarly, by substituting an equivalent amount of 9m-fiuoro-A -pregnadiene 1705,21 oxido-1lfi-ol-3,20- dione, 9u-chloro-A -pregnene-17,2l-oxido-l Idol-3,20- dione and 9a-c'nloro-A -pregnadiene-17a,2l-oxido-l 1 3- ol-3,20-dion-e for the 9a-fluoro-A -pregnene-17a,2l-oxido- 11fi,ol-3,20-dione in the procedure of Example 8, there is obtained 9a-fi-uoro-A -pregnadiene-17oa21-oxido-3,11, 20-trione (VIII), 9a-chloro-A -pregnene-17a,21-oxido- 3,11,20-trione (IX) and 9m-chloro-A -pregnadiene-17a, 21-oxido-3,11,20-trione (X), respectively.

EXAMPLE 9 A solution of 100 mg. of 9a-fiuoro-A -pregnene-170:,21- oxido-11p-ol-3,Z0-dione in 20 ml. methanol and 0.64 ml. of 8 /2% aqueous sulfuric acid is refluxed for 1.5 hours, After neutralization with sodium bicarbonate, the methanol is removed in vacuo, the resulting suspension extracted with chloroform, the chloroform extract dried over sodium sulfate and the solvent removed in vacuo. The resulting residue is recrystallized from acetonehexane and represents pure 9oc-fluoro-A -17fl-methyl-18- nor-l7a-pregnene-13a,21-oxido-11,6-ol-3,20-dione, of the following properties: M.P. about 252-254" (dec.); [a] |4-9 (c., 0.51 in CHCl EXAMPLE 1O To a solution of 69 mg. of 9a-fluoro-A -17B-methyl- 18-nor-17a-pregnene-l3a,21-oxido-1lB-ol-3,20-dione in 5 ml. of acetone is added with stirring 0.125 ml. of a solution containing 200 mg. of CrO and 320 mg. of sulfuric acid in 1 ml. water. After 20 minutes, a few drops of alcohol are added and the acetone removed in vacuo. The residual suspension is extracted with chloroform, the chloroform extract washed with water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and the solvent removed in vacuo. The residue, after recrystallization from aceone, represents pure 9: fluoro-A l7/3-methyl I70: pregnene-13u,21-oxido-3,11, ZO-trione of the following properties: M.P. about 226- 228"; [a] 18 (c., 0.81 in CHCl Kali} 235 my. (17,100), R231? OH, 5.69, 5.76, 5.94:, 6.16;.

AnaIysis.-Calcd. for C l-1 0 1 (360.41): C, 69.98; H, 6.99. Found: C, 69.96; H, 7.07.

In a similar manner, by substituting 9a-fiuoro-A -17 3- methyl-lh-pregnadiene l3 a,21-oxido-11fi-ol-3,20-dione 9C'L-ChlOIO-A -I7B-IIIGthYI 170a pregnene 13a,21-oxido- 11,8-ol-3,Z0-dione and 9oc-Chl0IO-A -17B-Inetl1Yl-17apregnadiene-:,21-0Xid0-11/3-ol-3,20-dione for the 9ozfluoro compound in the procedure of Example 10, there is obtained 9a-fluoro-A -17fi-methyl-17x-pregnadiene- 13a,2l-0XiCiO--3,11,20-tri01'1e (XVI), 9a-chloro-A -17fimethyl-17m-pregnene-13u,21-oxido-3,11,20trione (XVII) and 9oz-chloro-A -Uri-methyl 17cc pregnadiene-l3a,21- oxido-3,1l,20trione (XVIII), respectively.

EXAMPLE 11 Into a solution of mg. of 9a-fluoro-A -pregnene- 17oz, 21-oxido-11,6-ol-3,20-dione in 19 ml. of chloroform and 1 ml. of absolute alcohol is passed at 0 with stirring hydrogen fluoride gas until two layers develop (2 minutes). The resulting mixture is allowed to remain at 0 for 2 hours and is then neutralized by the addition of an aqueous suspension of sodium bicarbonate. The layers are separated and the chloroform phase washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue (about mg.) is dissolved in 1 mil. chloroform and 8 m1. benzene and chromatographed on 4 g. of acid-Washed alumina. Elution with chloroformbenzene (1:4) (300 m1.) gives a non-crystalline material, which is followed by a band of crystalline material (about 75 mg.) when the above eluant is replaced by chloroformbenzene (1 :1) (600 mil.). Crystallization of this material from acetone-hexane gives pure 9OL-fiuOI'O-A -17,B- methyl-17a-pregnadiene-11B,21-diol-3,20-dione of the following properties: M.P. about 181-182"; [a] (c., 1.28 in CHCl M53; 235 my. (17,700); Ami? 2.96, 5.86, 6.17;;

Analysis-Calcd. for C H O F (362.43): C, 69.61; H, 7.51; F, 5.37. Found: C, 69.77; H, 7.60; F, 5.22.

When the above reaction is terminated after minutes, Compound XI could be isolated as the major product.

Similarly, by substituting an equivalent amount of Compounds IV through VI for the 9u-flu0ro-A -l7B-methyll7a-pregnene-17a,2l-oxido-l1/3-ol-3,20-dione in Example 11, there is obtained 9a-fluoro-A -l7B-methyl-17apregnatriene 115,21 diol 3,20 dione (XX), 9a-chloro- A -17fl-methyl-17a-pregnadiene-1l,B,2l-diol-3,20 dione (XXI) and 9ot-chloro-A -l7B-methyl-l7a-pregnatriene- 11fi,21-diol-3,20-dione (XXI I), respectively.

These A -steroids can also be prepared from the l3u,2lepoxides (Compounds XI through XIV), as illustrated by the following example:

EXAMPLE 12 A solution of 200 mg. of 9a-fluoro-A -17fl-methyl-18- nor-17a-pregnene-13a,2l-oxido-llB-ol-3,20-dione in 19 ml. of chloroform and 1 ml. of alcohol is treated with hydrogen fluoride, as described in Example 11. The reaction mixture, upon chromatography and crystallization from acetone-hexane, furnishes pure 9e-fiuoro-A -17fimethyl-lh-pregnadiened1fi,21-diol-3,20 dione, identical in all respects with a specimen prepared by the procedure of Example 11.

Furthermore, Compounds XIX through XXII can be esterified by procedures illustrated in the following two examples:

EXAMPLE l3 50 mg. of 9a-fluoro-A -17fi-methyl-17a-pregnadiene- 1lp,21-diol-3,20-dione is dissolved in 0.786 ml. of pyridine containing 16.89 mg. of acetic anhydride, and the solution is allowed to remain at room temperature for 16 hours. The reagents are removed in vacuo and the residue consisting of the ll-monoacetate of 9oc-fiuoro-A -17fl-methyl- 18-nor-17a-pregnadiene-11fi,21-diol-3,20-dione is crystallized from acetone-hexane.

EXAMPLE l4 A solution of 9ot-fluoro-A -NIB-methyl-17a-pregnadiene-llfi,2l-diol-3,20-dione in 0.5 m1. of pyridine and 0.5 ml. of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo leaves a crystalline residue, which is recrystallized from acetone-hexane. The pure 115,21-diacetate has the following properties: M.P. about 118120 after melting at about 98100 and resolidification; [055 4-2023 (c., 0.89 in CI-ICI E31? no OH, 5.72, 5.80, 6.01, 6.17

Analysfs.Calcd. for C H O F (446.50): C, 67.23; H, 6.99. Found: C, 67.25; H, 7.05.

The monoacetate formed in Example 13 can be oxidized to the corresponding ll-ketone, as illustrated by the following example:

To a solution of mg. of 9a-fluoro-A -175-methyl- 17a-pregnadiene-11B,2l-diol-3,20-dione 21-acetate in 0.5 ml. of pyridine is added a suspension of 40 mg. of chromic acid in 0.5 ml. of pyridine. Eighteen hours later, water is added, and the mixture is extracted with chloroform, the chloroform solution throughly washed with water and the solvent removed in vacuo. The residue, upon recrystal- 10 lization from acetone-hexane, furnishes 9a-fluoro-A 17fi-methyl-17a pregnadiene-21-ol-3,11,20-trione 21-acetate.

This ester can be saponified in the usual manner, as by treatment with potassium carbonate in methanol, to yield the free 21-hydroxy steroid.

In a similar manner, the 21-monoacetates of 9oc-fl1101'0 A -17fl-methyl-17a pregnatriene 1113,21 diol 3,20- dione, 9a-chloro-A -17,8-methyl-17m pregnadiene 11B, 21-dio13,20-dione and 9a-chloro-A -l7fl-methyl-l7otpregnatriene-l1/3,2l-diol-3,20-dione can be oxidized to the 21-acetates of 9u-fiuoro-A -l7B-methyl-17ec-pregnatriene-2l-o1-3,l 1,20-trione (XXIV), 9oz-chloro A -17,8- methyl-l7u-pregnadiene-21-o1-3J1,20-trione (IOCV) and 9u-chloro-A -17,6-methyl-17oa-pregnatriene-2l-ol- 3,11, ZO-trione (XXVI), respectively.

The invention may be otherwise variously embodied within the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of A -pregnene-9B, 1lfl;l7a,2l dioxido 3,20 dione and A -pregnadiene-9t3,l1B;17a,2l-dioxido-3,20dione.

2. A compound selected from the group consisting of steroids of the general formulae and wherein R" is hydrogen, R' is selected from the group consisting of B-hydroxy and ,B-acyloxy, and together R and R is keto, X is a-halogen, and Y is selected from the group consisting of hydroxy and acyloxy, the acyloxy radical in both instances being the acyloxy radical of a hydrocarbon carboxylic acid having less then ten carbon atoms.

5. 9a-fluoro-A -17 3-methyl-17a-pregnadiene 1 15,21- diol-3,20 dione.

6. A process for preparing 9a-fiuoro-A -Eli-methyl- 17ot-pregnene 13u,21 oxido-llfi-ol-SQO-dione, which comprises heating 9a-fluoro-A -pregnene-17,21-oxido- 115-ol-3,20-dione with a dilute acid.

7. The process of claim 6, wherein the acid is sulfuric acid.

8. A process for preparing 9a-fluoro-A -17,8-rnethyl 17a-pregnadiene-11,8,21-dio1-3,20-dione, which comprises treating a compound selected from the group consisting of 9ot-fluo-ro-A -pregnene-17u,21-oXido-11,8-01-3 ,ZO-dione and 9a-fluoro-A -17B-methyL17a-pregnene-130,21-0Xid0 11B- ol-3,20-dione with hydrofluoric acid.

9. A process Winch comprises interacting a 2l-organic sulfonic acid ester of a steroid selected from the group consisting of 95,1lfl-epoxy-A -pregnane-17a,21-diol-3,20- dione and 95,11,G-epoxy-A -pregnadiene-17a,21-diol-3,20- dione with potassium fluoride and recovering the corresponding steroid selected from the group consisting of A pregnene-9B,11B;17ot,21dioXido-3,20-dione and A -pregnadiene-9B,1 1/3;17a,Z1-d1OXid0-3,20-d10n6.

10. A process which comprises interacting a steroid selected horn the group consisting of A -pregnene9fi,l 1B; 17a,21-dioxido-3,20-dione and A -pregnadiene-9fi,11fi;- 17a,2 1-dioXide-3,2()-dione with hydrogen halide and recovering the corresponding steroid selected from the group consisting of 9et-ha1o-A -pregnene-17a,21-oXido-11 3-01-3- 20-dione and Qu-haIQ-A -pregnadiene-17a,21-orrido-11B- ol-3,20-dione.

11. The process of claim 10, wherein the hydrogen halide is hydrogen chloride.

12. A process which comprises interacting 9a-fluorohydrocortisone 21-mesy1ate with potassium fluoride and recovering 9a-flu0ro-A -pregnene 17u,21 oxido-lLB-ol- 3,20-dione.

13. A process which comprises interacting 9u-flUOI'O- A -pregnadiene-1 lfl,17a,21-triO1-3,20-dione 21-n1esy1ate with potassium fluoride and recovering 9a-fluoro-A pregnadiene-17,21-0Xid0-11B-ol-3,20-dione.

14. A process which comprises interacting a steroid selected from the group consisting of 9oz-halo-A -pregnene- 17ot21-oxido-11fi-ol-3,20-dione and 9a-l1alo-A -pregnadiene-17e,21-oXido-11,B-ol-3,20-dione with an acid and recovering the corresponding steroid selected from the group consisting of 9a-halo-A -17B-methyl-17a-pregnene- 13a,2l-oxi lo-11fi-ol-3,2O dione and 9oz-hal0-A 17;?- methyl- 17a-pregnadiene-1 3 0L,21-O=XldO-1 1,8-01-3 ,ZO-dione.

15. A process which comprises treating a steriod selected from the group consisting of 9'ot-halo-A -17flmethyl-17a-pregnene-13a,21-oxido-11,8-ol-3,20-dione and 9a-halo-A -17,8-methyl-17a-pregnadiene-130:,21 oxido- 11,B-ol-3,20'-dione with hydrofluoric acid and recovering the corresponding steroid selected from the group consisting of 9a-halo-A -17p-rnethyl-17a-pregnadiene-115,21- diol-3,20-dione and 9a-halo-A 17,8-n1ethyl-17a-pregnatriene-11fi,21-diol-3 ,20 -dione.

16. A process which comprises treating a steriod selected from the group consisting of 9a-halo-A -pregnene- 17a,21-oXido-11fl-ol-3,20-dione and 9'a-halo-A -pregnadiene-17tx,21-0xido-11 3-o1-3,20-dione with hydrofluoric acid and recovering the corresponding steroid selected from the group consisting of 9a-halo-A -17B-methyl- 17a-pregnatriene-11B,21-diol 3,20 dione, and 9'ot-halo A -17fi-1nethyl-17a-pregnatriene 115,21 did-3,20- dione.

References Cited in the file of this patent UNITED STATES PATENTS Bailey et a1. Dec. 23, 1958 Bailey et a1. Apr. 12, 1960 OTHER REFERENCES UNITED STATES IIIATENT OFFICE CERTIFICATION OF CORRECTION 'atent No. 3 OO7,925 November 7,, 1961 Josef Fried et al that error appears in the above numbered pat- It is hereby certified d that the said Letters Patent should read as ent requiring correction an corrected below.

Column 3" the third formula should appear as follows instead of as in the patent:

column ll line 32 for "'dioxide read di0xid0 Signed and sealed this 29th day of May 1962;,

(SEAL) Attest:

ERNEST W. SWIDER Attesting Officer DAVID L. LADD Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF $4-PREGNENE-9B, 11B,17A,21-DIOXIDO -3,20-DIONE AND $1,4-PREGNADIENE-9B,11B,17A,21-DIOXIDO-3,20-DIONE.
 2. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE GENERAL FORMULAE 